CDH4/UBA1/RBMX axis promotes polycystic ovary syndrome progression through YAP1 activation

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of childbearing age. In addition, it is a heterogeneous disease with numerous etiologies, multiple levels, and uneven manifestation. In patients with PCOS, the number of antral follicles is abnormally increased. Several studies indicate and preliminarily support that Hippo pathway abnormalities may contribute to PCOS development by promoting excessive antral follicle proliferation. Moreover, the key Hippo pathway effector, Yes-associated protein 1 (YAP1), contributes to PCOS susceptibility. Furthermore, dysfunction of ovaries in patients with PCOS leads to irregular granulosa cell (GC) growth, which can affect ovulation and cause infertility. Nevertheless, few studies have investigated the key mechanism regulating Hippo activation in PCOS. Hippo-associated gene sets and publicly available sequencing databases were used to screen potential PCOS-driving genes, and cadherin 4 (CDH4, R-cadherin) was found to exhibit abnormally high expression in ovarian granulosa cells. Functional studies were conducted to investigate the effects of CDH4 inhibition on PCOS-related ovarian function. A lower CDH4 level ameliorated ovarian function in patients with PCOS by decreasing chronic inflammation and modulating mitochondrial function and apoptosis in GCs. Mechanistically, CDH4 interacts with UBA1 and RBMX, increasing the ubiquitin-dependent degradation of RBMX and finally resulting in the transcriptional activation of YAP1. These results highlight the pivotal role of CDH4 in PCOS, which is achieved through the regulation of the Hippo–YAP1 signaling axis. This study demonstrates that CDH4 plays a pivotal role in PCOS pathogenesis by regulating the Hippo–YAP1 signaling axis. The finding that reduced CDH4 could enhance the prognosis of individuals with PCOS by regulating ovarian GC activity could potentially inform novel treatment strategies.